NY Prostate Cancer Conference - C. Bangma - Session 3: Predicting indolent and low risk prostate cancer


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  • erspc 616 suitable Median fu 4 years Sweden finland, netherlands, Well documented from erspc NB: de helft van de patienten onder watchful waiting is behandeld na 5 jaar CONCLUSIE: ER STERFT NAUWELIJKS IEMAND ONDER WAWA IN ERSPC (DUS PRIAS SUITABLE, MAAR NIET VERVOLGD ONDER PRIAS SCHEMA)
  • Volume in diagnosed cancersJ Urol. 1993 Jun;149(6):1478-81.5 year followup. Still one third is ‘relevant ‘cancer Is tumor volume an independent predictor of progression following radical prostatectomy? A multivariate analysis of 185 clinical stage B adenocarcinomas of the prostate with 5 years of followup. Epstein JI , Carmichael M , Partin AW , Walsh PC . Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Comment in: Abstract Tumor volume has been shown to be proportionate to Gleason grade, capsular penetration, seminal vesicle invasion, lymph node metastases and capsular margins of resection. Because these variables are often interrelated, it is crucial to determine which of these parameters provides independent prediction of prognosis in prostate cancer. The current study analyzed 185 men who underwent radial retropubic prostatectomy for clinical stage B adenocarcinoma of the prostate. Patients with seminal vesicle invasion or lymph node metastases were excluded, since these findings are almost invariably associated with progression. All patients were followed for a minimum of 5 years after radical prostatectomy. Only 2 men received postoperative adjuvant therapy. At 5 years after radical prostatectomy 58 men (31%) experienced progression, defined by either an elevated postoperative serum prostate specific antigen level, local recurrence or distant metastases. Although by themselves capsular penetration, tumor volume and per cent of the prostate involved by tumor predicted progression, in a stepwise regression analysis they did not provide independent prognostic information. In this multivariate analysis Gleason score was the best predictor of progression (p < 0.0001); surgical margin was the only other variable that enhanced prediction, although it was less influential than grade (p = 0.018). This strong predictability provided by Gleason score was all the more impressive given the relatively few patients in our study with either low or high grade tumor. Although an accurate preoperative assessment of tumor volume remains desirable for the management of patients with prostate cancer, our study demonstrates that measurement of tumor volume in radical prostatectomy specimens need not be performed as part of the routine pathological analysis of radical prostatectomy specimens, since it does not provide additional information beyond that of Gleason score and the status of capsular margins.
  • Cystoprostatectomy specimens were evaluated in 66 male patients operated on for a pathological condition of the bladder with no evidence of prostatic malignancy on preoperative clinical assessment. There were 38 prostate cancers identified in 25 of 66 patients (38 per cent). Multiple foci of adenocarcinoma were noted in 10 of 25 patients (40 per cent). The mean tumor volume was 0.11 cc, with half of the cancers being less than or equal to 0.01 cc in volume. All 38 cancers were completely localized to the prostate and exact anatomical sites of origin for each of the cancers within the prostate were mapped. Whereas anatomical distribution of the cancers in the anteroposterior dimension was roughly uniform, a distinct predominance of apical prostatic cancers was observed. Possible anatomical explanations and implications of these findings in terms of the apical surgical margins at radical prostatectomy and cystoprostatectomy, and the new technologies currently available for diagnosis of prostate cancer are discussed
  • Clinical: Damico 2001 in which in ca 1800 men from 44 institutes mortality was related to pretreatment parameters of low-intermediate and high risk … Third, the predictions of PCSM using the pretreatment risk groups in this study are only applicable to patients with clinically localized prostate cancer undergoing RP or RT therapy….
  • National Comprehensive Cancer Network. Prostate Cancer. Clinical Practice Guidelines in Oncology—v.1.2010. Available at: http://www.nccn.org (free registration and log-in required). Accessed May 5, 2010. 32. Parker C, Muston D, Melia J, Moss S, Dearnaley D. A
  • At initial screening the fraction of positive biopsies was 29% (541 of 1850). Applying an additional P(biop+) cut-off of 12.5% implied that 613 of the 1850 men (33%) would not have been biopsied. This would result in an increase in the positive predictive value (PPV) to 38% (468 of 1237). At repeat screening a similar P(biop+) cut-off would result in an increase in the PPV from 19% (225 of 1201) to 25% (188 of 760). Thirteen percent of PC cases would not have been diagnosed, of which 70% (initial screening) and 81% (repeat screening) could be considered as potentially indolent. None of the deadly PC cases would have been missed. A PSA cut-off of 4.0 ng/ml resulted in similar numbers of biopsied cases saved but considerably higher numbers of missed diagnoses. Bergh: smaller prostates tend to be underestimated risk in pcpt. Nb no black men
  • Evaluation of 111 nomograms in 2008 = playing on safe, defensive
  • selectie
  • The ERSPC RC performs well in a clinical setting. phi plus DRE outperform the classical approach for risk assessment (PSA plus DRE outcome). There is additional value of phi to the ERSPC RC (not significant), however specificity increases considerably. The combination of phi and DRE, results in equal performance (expressed as AUC) with the ERSPC RC for HG PC but circumvents the need of prostate volume assessment. Semjonov barcelona 2011 BJU Int. 2010 Jul;106(2):280-6. Epub 2009 Nov 3. The value of EZH2, p27(kip1), BMI-1 and MIB-1 on biopsy specimens with low-risk prostate cancer in selecting men with significant prostate cancer at prostatectomy. Wolters T , Vissers KJ , Bangma CH , Schröder FH , van Leenders GJ . Department of Urology, Erasmus Medical Center, Rotterdam, the Netherlands. t.wolters@erasmusmc.nl Abstract OBJECTIVE: To assess the additional prognostic value of the molecular markers EZH2, MIB-1, p27(kip1) and BMI-1 on needle biopsies from men with low-risk prostate cancer, as this disease in needle biopsies shows a heterogeneous clinical outcome, and while it is known that the expression of these tissue markers is predictive of the clinical outcome after radical prostatectomy (RP) their value in prostate biopsies is largely unknown. PATIENTS AND METHODS: The study included men participating in a screening study, diagnosed with low-risk prostate cancer and subsequently treated with RP. Immunohistochemical staining for EZH2, MIB-1, p27(kip1) and BMI-1 on the needle biopsies were (semi)quantitatively scored and expression levels were related to significant disease at RP. Clinical low-risk prostate cancer was defined as a prostate-specific antigen (PSA) level of < or =10 ng/mL, clinical T-stage < or =2, biopsy Gleason score < or =6, a PSA density of <0.20 ng/mL/g and two or fewer positive cores. Significant PC at RP was defined as presence of any of extracapsular extension, Gleason pattern 4/5, or tumour volume > or =0.5 mL. RESULTS: In all, 86 biopsy specimens were included; there was high EZH2 expression (>1.0%) in 42% and a low p27(kip) expression (<90%) in 63%. Significant disease was present in 44 (51%) RP specimens. A high EZH2 (odds ratio 3.19, P = 0.043) and a low p27(kip1) (4.69, P = 0.036) were independent predictors for significant prostate cancer at RP. CONCLUSIONS: The determination of EZH2 and p27(kip1) on diagnostic needle biopsies supports the selection of men with indolent prostate cancer at RP. Especially p27(kip1) could improve the pretreatment risk assessment of patients with low-risk prostate cancer.
  • NY Prostate Cancer Conference - C. Bangma - Session 3: Predicting indolent and low risk prostate cancer

    1. 1. Predicting indolent and low risk prostate cancer Chris Bangma New York, april 2011
    2. 2. Retrospective findings in screen-detected ‘PRIAS-suitable’ PCa (n = 616) (Van den Bergh et al, Eur Urol,2009) Many cases of prostate cancer are not lethal if left untreated
    3. 3. What is that: ‘indolent’ ? <ul><li>What the patient wants: no symptoms during life </li></ul><ul><li>What the scientist wants: a molecular pattern </li></ul><ul><li>What the clinician wants: a recognisable phenomenon </li></ul><ul><li>Surrogate endpoints </li></ul>
    4. 4. Preparing the stage for indolent low risk thinking Pivotal papers 1: Epstein 1993 < 0.15 ng/ml/ml PSAD < 50 % per core Cancer < 3 Number pos biopsy cores < 10 ng/ml PSA < 7 < 7 Gleason sum < 0.5 ml Tumour Volume In pretreatment after biopsies In radical prostatectomy specimen
    5. 5. Preparing the stage for indolent low risk thinking Pivotal papers 2: Kabalin 1989 <ul><li>Unsuspected Pca in 66 cystoprostatectomy specimens </li></ul><ul><li>38 % Pca, mean volume 1.1 ml (half of these < 0.01 ml) </li></ul>
    6. 6. Preparing the stage for indolent low risk thinking Pivotal papers 3: d’Amico 2001 <ul><li>Mortality related to pretreatment parameters </li></ul><ul><li>1800 men, 44 institutes </li></ul>‘… the pretreatment risk groups in this study are only applicable to patients with clinically localized prostate cancer undergoing RP or RT therapy….’
    7. 7. Predicting indolence once there is cancer: making a nomogram Clinical diagnosis (at time of tumor diagnosis) PSA < 15 PSAD < 0.2 Pos cores <3 Pathological diagnosis: One focus < 5 mm Pca Biological diagnosis: No progression during lifetime, PSADT > 10 years 1 2 3 4 1+2+3+4 = indolent disease Focal Insignificant Minimal Pathologic diagnosis Biological diagnosis clinical diagnosis
    8. 8. Incidence of histologic indolent disease in clinical series and in the general population Indolent = PSA< 10ng/ml, tumour volume < 0.5 ml, Gleason < 7 10 48 6 20 10 Percentage of indolent disease screening screening clinical clinical clinical Origin 2196 247 1254 409 222 Number of patients with Radical Prostatectomy Catalona J.Urol. 2006 Steyerberg J.Urol. 2007 Huland Eur.Urol. 2003 Kattan J.Urol. 2003 Noguchi J.Urol. 2001 series
    9. 9. Indolence versus low risk: is there a difference? NCCN guidelines 2010 or and 8-10 > 20 3a High risk 7 10-20 2b-2c Intermediate risk 2-6 < 10 1-2a Low risk < 3 cores pos < 50 % ca PSAD< 0.15 < 6 < 10 1 Very low risk other Gleason PSA T-stage
    10. 10. Which nomograms do we have predicting indolence? 0.73 0.77 0.65-0.79 Discriminative ability (AUC) 1 pos core only Early hormones Specific parameters + -- + + + + + - + + + + + + - + + + + - PSA Gleason Volume Biopsy detail Age - + + - General population Nakanishi Cancer 2007 Kattan, Cancer 2008 Steyerberg, J.Urol. 2007 Kattan, J.Urol 2007
    11. 11. Man 60 years old, PSA 4,0 ng/ml, gland volume 40 ml, DRE = T1c, 1 pos biopsy with 5 mm cancer and 120 mm benign tissue, no endocrine therapy 32 % 92 % (10 years DSS) 65 % (+/- 5) 22 % (23 % in revised nomogram) Indolent disease Nakanishi Cancer 2007 Kattan Cancer 2008 Steyerberg J.Urol. 2007 Kattan J.Urol. 2003  
    12. 12. Predicting a positive biopsy and predicting indolence go hand in hand… <ul><li>A risk based strategy improves PSA driven detection of prostate cancer, Roobol, Vickers, et al, 2010 </li></ul><ul><ul><li>DRE, PSA, TRUS Volume </li></ul></ul><ul><ul><li>Performing biopsy at 12.5 % risk or more reduces 33 % of number of biopsies, missing 13 % of (predominantly indolent) tumours </li></ul></ul><ul><li>The Prostate Cancer Prevention Trial and European Randomized Study of Screening for Prostate Cancer risk calculators indicating a positive prostate biopsy: a comparison. Van den Bergh et al , 2008 </li></ul>
    13. 13. How to use nomograms <ul><li>‘… Clearly, no risk instrument should be used in isolation to direct patients towards or away from treatment alternatives…’ Cooperberg, Cancer 2008 </li></ul><ul><li>Factors not measured by current models: baseline quality of life, comorbidity , life expectancy, treatment preference </li></ul>Albertsen P C et al. JCO 2011;29:1335-1341
    14. 14. Who do we need to treat? <ul><li>Tumour biology versus host biology </li></ul><ul><li>Tumour lead time 8-13 years </li></ul><ul><li>Patient with life expectancy of >10 years </li></ul>10
    15. 15. Is a nomogram being used? <ul><li>Beyond the technical evaluation: the practical evaluation: </li></ul><ul><ul><li>When will a patient allow for accepting calculator based recommendations? And when does he refuse? </li></ul></ul><ul><li>Compliance with biopsy recommendations by a prostate cancer risk calculator. Van Vugt et al abstract, 2011 EAU </li></ul><ul><ul><li>Both urologists and patients were compliant in 245/291 cases (84%). </li></ul></ul><ul><ul><li>38 of the 119 (31%) were non-compliant with ‘no biopsy’ recommendations. </li></ul></ul><ul><ul><li>Urologists reason for non-compliance was an elevated PSA (≥3ng/ml, 87% = 33/38) </li></ul></ul>
    16. 16. Riskindicator # 6 calculating individual probability on indolent Pca based on population data Simplicity: www.uroweb.org
    17. 17. Compliance to therapy advise in low risk Van Vugt 2011 <ul><li>Prospective analysis of Risk Calculator in 5 Dutch hospitals </li></ul><ul><li>Inclusion criteria: clinical stage T1c, T2a-c, PSA < 20ng/ml, <50% positive sextant biopsy cores, ≤20 mm cancer, ≥ 40 mm benign tissue, Gleason ≤ 3 + 3, no urological symptoms (except for urinary symptoms) </li></ul><ul><li>213 low risk </li></ul><ul><li>50 potentialy indolent on Risk Calculator (> 70 %) </li></ul><ul><li>163 advised active treatment, 50 Active Surveillance </li></ul><ul><li>Most patients (42/50, 84%) compliant with an AS recommendation. </li></ul><ul><li>49 choose AS in contrast to AT recommendations (49/163, 30%) </li></ul>
    18. 18. Improving nomograms for individualised risk assessment <ul><li>Longer observation </li></ul><ul><li>Validation in independent data sets </li></ul><ul><li>Incorporating new prognostic parameters </li></ul><ul><ul><li>Kallekreins (Vickers, Roobol, JCO 2010) </li></ul></ul><ul><ul><li>PHI (with Risk Calc: specificity 40>>58 %, Roobol 2011) </li></ul></ul><ul><ul><li>PCA3 </li></ul></ul><ul><ul><li>Histology </li></ul></ul><ul><ul><li>Imaging </li></ul></ul><ul><ul><li>? Molecular markers? </li></ul></ul><ul><li>Nomograms on FUTURE risk instead of current risk. </li></ul>
    19. 19. Conclusions on nomograms for indolent and low risk disease <ul><li>Dependent on population used </li></ul><ul><li>Accuracy increases with time </li></ul><ul><li>Increasing specificity of detection tools should decrease incidence of indolent cancers </li></ul><ul><li>Implementation increases with patient/doctor expectation </li></ul><ul><li>Which nomogram alters practise? The one that is being used…. </li></ul>
    20. 20. World symposium on Active Surveillance Rotterdam January 12-13 th 2012